Long non-coding RNAs in the tumor immune microenvironment of non-small cell lung cancer: mechanisms and clinical translational perspectives

Immune checkpoint inhibitors (ICIs) have improved outcomes for patients with non-small cell lung cancer (NSCLC), yet their efficacy is hindered by the immunosuppressive and therapy-resistant tumor immune microenvironment (TIME). Long non-coding RNAs (lncRNAs) have emerged as critical regulators of immune signaling, ferroptosis, and cellular interactions within the TIME, highlighting their potential roles in shaping ICI response. LncRNAs modulate multiple layers of antitumor immunity in NSCLC. They regulate immune evasion through PD-1/PD-L1 signaling (SNHG12, SChLAP1, PCAT1, NEAT1), influence T-cell survival and differentiation (NKILA, MIR17HG), and affect macrophage phagocytic checkpoints (KCTD21–AS1–CD47). LncRNAs also integrate ferroptosis, stemness, and metabolic rewiring, as exemplified by RGMB-AS1 and AC026356.1. Several lncRNAs—including ADAMTS9–AS2, PCBP1–AS1, LY6K-AS, FAM207BP, and LINC01833—exhibit prognostic or predictive significance for immunotherapy. Exosomal lncRNAs further offer minimally invasive tools for liquid biopsy and longitudinal monitoring. Translational opportunities include nucleic acid therapeutics, innovative delivery systems, and rational combinations of ICIs with ferroptosis inducers or metabolic modulators. Multi-omics and spatial transcriptomics are essential to clarify mechanisms and identify high-confidence clinical candidates. LncRNAs are central regulators of NSCLC antitumor immunity and determinants of ICI sensitivity. Their dual potential as biomarkers and therapeutic targets underscores the need for mechanistic validation, multi-omics integration, and prospective clinical trials to accelerate their translation into NSCLC immunotherapy.